Ezetimibe: a selective inhibitor of cholesterol absorption

Abstract

Ezetimibe is a novel selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol. Ezetimibe undergoes glucuronidation to a single metabolite and is localized in the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and the glucoronide ensures repeated delivery to the site of action and limits peripheral exposure. Ezetimibe does not affect the absorption of fat-soluble vitamins or triglycerides. Results from pre-clinical studies in various animal models have shown the lipid-lowering and anti-atherosclerotic properties of ezetimibe as a single agent, and a synergistic effect when combined with a statin. In cholesterol-fed rhesus monkeys, ezetimibe reduced both plasma cholesterol (ED₅₀ = 0·0005 mg.kg⁻¹.day⁻¹) and low-density lipoprotein cholesterol levels in a dose-dependent manner. In apo F knockout mice, ezetimibe reduced serum cholesterol more than 50% and decreased carotid (97%) and aortic (47–87%) atherosclerosis. Ezetimibe inhibited the rise of plasma cholesterol in cholesterol-fed dogs (ED₅₀ = 0·007 mg.kg⁻¹.day⁻¹). Co-administration of ezetimibe and lovastatin in chow-fed dogs synergistically reduced plasma cholesterol to levels lower than those achieved with either agent alone ( \(P{<}0{\cdot}05\) ). These results suggest that ezetimibe combined with a statin may similarly reduce plasma cholesterol levels in patients with hypercholesterolaemia.